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This study evaluated the feasibility and efficacy of three postoperative adjuvant chemotherapy regimens for endometrial cancer. Endometrioid cancer patients with intermediate‐risk stage I and II or high‐risk stage III and IV disease were randomly assigned to receive six cycles of either paclitaxel‐epirubicin‐carboplatin (TEC), paclitaxel‐anthracycline (doxorubicin)‐carboplatin (TAC), or dose‐dense paclitaxel‐carboplatin (ddTC). The primary end‐point was the completion rate (CRate) of six cycles of treatment. The secondary end‐points were progression‐free survival (PFS) and overall survival (OS). One hundred and one patients were treated as follows: 33 received TEC, 33 TAC, and 35 ddTC. The CRates for TEC, TAC, and ddTC were 94%, 64%, and 69%, respectively (P =.005). The TEC CRate was significantly higher than for the other two groups. However, the PFS and OS outcomes were not statistically different between the three groups. The 2‐year survival rates were 94%, 97%, and 97% for TEC, TAC, and ddTC, respectively. When compared to the current standard treatments for endometrial cancer, TEC is a promising candidate for a phase III trial based on its significantly superior CRate and equivalent PFS and OS. This study is registered with UMIN Clinical Trials Registry (UMIN000008911). [ABSTRACT FROM AUTHOR]

Improved surgical techniques and immunosuppressant medications for organ transplantation have resulted in a significant increase in the number of women undergoing renal transplantation. Peritoneal dialysis (PD), a common supportive therapy for chronic renal failure, is also used in cases of renal transplantation failure. Herein, we report the first case of a rare total conventional laparoscopic gynecologic hysterectomy performed for endometrial cancer in a patient undergoing life-supportive PD as a result of renal transplantation failure. No unusual intraoperative complications were experienced, but post-surgical peritoneal leakage was observed. We reviewed the literature of alternative surgical methods of hysterectomy for endometrial cancer in patients who had undergone renal transplantation and were undergoing PD at the time of the hysterectomy. Laparoscopic hysterectomy could be safe in a renal transplantation patient receiving PD if injury to the transplanted ureter and renal artery is avoided by recognizing the patient's anatomy and PD leakage is averted by careful peritoneum suture and avoiding contact with the PD catheter. [ABSTRACT FROM AUTHOR]

Several molecular targeting drugs are being evaluated for endometrial cancer; selecting patients whose cancers are sensitive to these agents is of paramount importance. Previously, we developed the cancer tissue-originated spheroid method for primary cancer cells taken from patients' tumors as well as patient-derived xenografts. In this study, we successfully prepared and cultured cancer tissue-originated spheroids from endometrial cancers. Characteristics of the original tumors were well retained in cancer tissue-originated spheroids including morphology and expression of p53 or neuroendocrine markers. We screened 79 molecular targeting drugs using two cancer tissue-originated spheroid lines derived from endometrioid adenocarcinoma grade 3 and serous adenocarcinoma. Among several hits, we focused on everolimus, a mammalian target of rapamycin complex 1 inhibitor, and YM155, a survivin inhibitor. When sensitivity to everolimus or YM155 was assessed in 12 or 11 cancer tissue-originated spheroids, respectively, from different endometrial cancer patients, the sensitivity varied substantially. The cancer tissue-originated spheroids sensitive to everolimus showed remarkable suppression of proliferation. The phosphorylation status of the mammalian target of rapamycin complex 1 downstream molecules before and after everolimus treatment did not predict the effect of the drug. In contrast, the cancer tissue-originated spheroids sensitive to YM155 showed remarkable cell death. The effect of YM155 was also confirmed in vivo. The histological type correlated with YM155 sensitivity; non-endometrioid adenocarcinomas were sensitive and endometrioid adenocarcinomas were resistant. Non-canonical autophagic cell death was the most likely cause of cell death in a sensitive cancer tissue-originated spheroid. Thus, sensitivity assays using cancer tissue-originated spheroids from endometrial cancers may be useful for screening drugs and finding biomarkers. [ABSTRACT FROM AUTHOR]

This report utilizes a novel proteomic method for discovering potential therapeutic targets in endometrial cancer. We used a biotinylation-based approach for cell-surface protein enrichment combined with isobaric tags for relative and absolute quantitation (iTRAQ) technology using nano liquid chromatography-tandem mass spectrometry analysis to identify specifically overexpressed proteins in endometrial cancer cells compared with normal endometrial cells. We identified a total of 272 proteins, including 11 plasma membrane proteins, whose expression increased more than twofold in at least four of seven endometrial cancer cell lines compared with a normal endometrial cell line. Overexpression of bone marrow stromal antigen 2 (BST2) was detected and the observation was supported by immunohistochemical analysis using clinical samples. The expression of BST2 was more characteristic of 118 endometrial cancer tissues compared with 59 normal endometrial tissues ( p < 0.0001). The therapeutic effect of an anti-BST2 antibody was studied both in vitro and in vivo. An anti-BST2 monoclonal antibody showed in vitro cytotoxicity in BST2-positive endometrial cancer cells via antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity. In an in vivo xenograft model, anti-BST2 antibody treatment significantly inhibited tumor growth of BST2-positive endometrial cancer cells in an NK cell-dependent manner. The anti-BST2 antibody had a potent antitumor effect against endometrial cancer both in vitro and in vivo, indicating a strong potential for clinical use of anti-BST2 antibody for endometrial cancer treatment. The combination of biotinylation-based enrichment of cell-surface proteins and iTRAQ analysis should be a useful screening method for future discovery of potential therapeutic targets. [ABSTRACT FROM AUTHOR]

The objective of this study was to assess the value of intraoperative frozen section (IFS) diagnosis for myometrial invasion and histology of endometrial cancer using the revised International Federation of Gynecology and Obstetrics (FIGO) staging system.The medical records of 303 patients with endometrial cancer who underwent surgery with intraoperative diagnosis at the Osaka University Hospital between January 1999 and December 2008 were reviewed. Intraoperative frozen section diagnosis was retrospectively analyzed for the accuracy rates of myometrial invasion and histology compared with the final diagnosis and with preoperative prediction by magnetic resonance imaging (MRI) and endometrial curettage.When using the previous FIGO staging system, the accuracy rate of IFS for the diagnosis of myometrial invasion was 77%, whereas the accuracy rate of preoperative prediction by MRI was 54%. However, using the newly revised FIGO staging system for myometrial invasion, the accuracy rate of IFS was 87% and the preoperative prediction by MRI was 82%. The accuracy rate of IFS for the diagnosis of histology was 71%, whereas the accuracy rate of preoperative prediction by endometrial curettage was 68%.Although under the previous FIGO staging system IFS diagnosis was significantly more accurate than preoperative prediction by MRI, when using the newly revised FIGO staging system, there are no significant differences between the values of preoperative and intraoperative diagnoses. The accuracy of IFS, however, trends to be slightly better than the preoperative procedures of MRI and endometrial surface biopsy. Thus, IFS diagnosis is still useful for directing primary operative management. [ABSTRACT FROM AUTHOR]

Background: The coexistence of hematological malignancy with endometrial cancer is a rare phenomenon. We report a case of coexistence of endometrial cancer with follicular lymphoma which we suspected preoperatively and diagnosed during surgery by a multidisciplinary intraoperative assessment. Case presentation: A 67-year-old woman was referred to our hospital due to a suspicion of an endometrial cancer. Endometrial biopsy revealed grade 1 endometrioid adenocarcinoma. MRI showed invasion of the tumor into the outer half of the myometrium, and abdominal CT showed para-aortic and atypical mesentery lymphadenopathy which was suspected to be metastasis of endometrial cancer or malignant lymphoma. Abdominal hysterectomy with bilateral salpingo-oophorectomy, pelvic and para-aortic lymphadenectomy, partial omentectomy, and mesentery lymph node biopsy for endometrial cancer were performed. The mesentery and para-aortic lymph nodes that were sent for frozen section analysis showed no metastasis of the endometrial cancer. We simultaneously conducted an unusual intraoperative emergent four-color flow cytometry and intraoperatively diagnosed a B cell lymphoma in the mesenteric lymph nodes. Because this multidisciplinary assessment, we were able to avoid an unnecessary intestinal resection. The final pathological diagnosis was an endometrioid carcinoma (G1, FIGO stage IA), with a synchronous follicular lymphoma. Conclusion: Although a rare event in endometrial cancer surgery, it is necessary to be alert to the possibility of a synchronous lymphoma in cases of unusual site adenopathy. [ABSTRACT FROM AUTHOR]

Objective: We evaluated association of prognosis of endometrial carcinoma patients and treatment-free intervals (TFIs). Study Design: We compared the effectiveness of second-line chemotherapy performed for patients with TFIs of 6-12 months and 12 or more months following a first-line chemotherapy based on taxane (paclitaxel) and carboplatin, with or without the anthracycline (TC). Results: Progression-free and overall survivals were significantly shorter in patients with TFIs of 6-12 months than those with TFIs of 12 or more months. Among the patients who received similar second-line chemotherapy, response rates of 15 patients with TFIs of 12 or more months and 7 patients with TFIs of 6-12 months were 67% and 43%, respectively. Progression-free survival was significantly worse in those with TFIs of 6-12 months (median, 7 months) than those with TFIs of 12 or more months (median, 12 months). Conclusion: Our small retrospective analysis suggests that recurrent endometrial carcinomas with TFIs of 6-12 months can be regarded as being partially sensitive to TC-based chemotherapy. [Copyright &y& Elsevier]

Abstract Objective The anti-thrombogenic effects of statins and aspirin have been reported in various malignancies but have not been well examined in endometrial cancer. This study examined the association between statin and/or aspirin use and venous thromboembolism (VTE) risk in endometrial cancer. Methods This is a multi-center retrospective study examining 2527 women with endometrial cancer between 2000 and 2015. Statin and aspirin use at diagnosis was correlated to VTE risk during follow-up on multivariable analysis. Results There were 132 VTE events with a 5-year cumulative incidence rate of 6.1%. There were 392 (15.5%) statin users and 219 (8.7%) aspirin users, respectively. On multivariable analysis, statin use was associated with an approximately 60% decreased risk of VTE when compared to non-users (5-year cumulative rates 2.5% versus 6.7%, adjusted-hazard ratio [HR] 0.42, 95% confidence interval [CI] 0.19–0.92, P = 0.030) whereas aspirin did not demonstrate statistical significance (2.0% versus 6.5%, adjusted-HR 0.54, 95%CI 0.19–1.51, P = 0.24). There was a trend of joint effect between statin and aspirin although it did not demonstrate statistical significance: VTE risks for dual statin/aspirin user (adjusted-HR 0.27, 95%CI 0.04–2.07), statin alone (adjusted-HR 0.40, 95%CI 0.18–0.93), and aspirin alone (adjusted-HR 0.51, 95%CI 0.16–1.64) compared to non-use after adjusting for patient characteristics, tumor factors, treatment types, and survival events (P -interaction = 0.090). When stratified by statin type, simvastatin demonstrated the largest reduction of VTE risk (5-year cumulative rates 1.1% versus 6.7%, adjusted-HR 0.17, 95%CI 0.02–1.30, P = 0.088). Obesity, absence of diabetes mellitus, type II histology, and recurrent disease were the factors associated with decreased VTE risk with statin use (all, P -interaction<0.05). Conclusion Our study suggests that statin use may be associated with decreased risk of VTE in women with endometrial cancer. Highlights • Association of statins and VTE remains understudied in endometrial cancer. • Statin use may be associated with decreased risk of VTE in endometrial cancer. • Obese non-diabetic women may benefit from statin use to reduce VTE risk. • Women with aggressive tumors may benefit from statin use to reduce VTE risk. [ABSTRACT FROM AUTHOR]

Objective To examine survival of women with stage I–II endometrioid endometrial cancer whose peritoneal cytology showed malignant or atypical cells (abnormal peritoneal cytology). Methods This is a multi-center retrospective study examining 1668 women with stage I–II endometrioid endometrial cancer who underwent primary hysterectomy with available peritoneal cytology results between 2000 and 2015. Abnormal peritoneal cytology was correlated to clinico-pathological characteristics and oncological outcome. Results Malignant and atypical cells were seen in 125 (7.5%) and 58 (3.5%) cases, respectively. On multivariate analysis, non-obesity, non-diabetes mellitus, cigarette use, and lympho-vascular space invasion were independently associated with abnormal peritoneal cytology (all, P < 0.05). Abnormal peritoneal cytology was independently associated with decreased disease-free survival (hazard ratio 3.07, P < 0.001) and cause-specific survival (hazard ratio 3.42, P = 0.008) on multivariate analysis. Abnormal peritoneal cytology was significantly associated with increased risks of distant-recurrence (5-year rates: 8.8% versus 3.6%, P = 0.001) but not local-recurrence (5.2% versus 3.0%, P = 0.32) compared to negative cytology. Among women with stage I disease, abnormal peritoneal cytology was significantly associated with an increased risk of distant-recurrence in the low risk group (5-year rates: 5.5% versus 1.0%, P < 0.001) but not in the high-intermediate risk group (13.3% versus 10.8% P = 0.60). Among 183 women who had abnormal peritoneal cytology, postoperative chemotherapy significantly reduced the rate of peritoneal recurrence (5-year rates: 1.3% versus 9.2%, P = 0.039) whereas postoperative radiotherapy did not (7.1% versus 5.5%, P = 0.63). Conclusion Our study suggests that abnormal peritoneal cytology may be a prognostic factor for decreased survival in women with stage I–II endometrioid endometrial cancer, particularly for low-risk group. [ABSTRACT FROM AUTHOR]

Objective Although a fraction of endometrial hyperplasia cases have concurrent endometrial carcinoma, patient characteristics associated with concurrent malignancy are not well described. The aim of our study was to identify predictive clinico-pathologic factors for concurrent endometrial carcinoma among patients with endometrial hyperplasia. Methods A case–control study was conducted to compare endometrial hyperplasia in both preoperative endometrial biopsy and hysterectomy specimens (n = 168) and endometrial carcinoma in hysterectomy specimen but endometrial hyperplasia in preoperative endometrial biopsy (n = 43). Clinico-pathologic factors were examined to identify independent risk factors of concurrent endometrial carcinoma in a multivariate logistic regression model. Results The most common histologic subtype in preoperative endometrial biopsy was complex hyperplasia with atypia [CAH] (n = 129) followed by complex hyperplasia without atypia (n = 58) and simple hyperplasia with or without atypia (n = 24). The majority of endometrial carcinomas were grade 1 (86.0%) and stage I (83.7%). In multivariate analysis, age 40–59 (odds ratio [OR] 3.07, p = 0.021), age ≥ 60 (OR 6.65, p = 0.005), BMI ≥ 35 kg/m 2 (OR 2.32, p = 0.029), diabetes mellitus (OR 2.51, p = 0.019), and CAH (OR 9.01, p = 0.042) were independent predictors of concurrent endometrial carcinoma. The risk of concurrent endometrial carcinoma rose dramatically with increasing number of risk factors identified in multivariate model (none 0%, 1 risk factor 7.0%, 2 risk factors 17.6%, 3 risk factors 35.8%, and 4 risk factors 45.5%, p < 0.001). Hormonal treatment was associated with decreased risk of concurrent endometrial cancer in those with ≥ 3 risk factors. Conclusions Older age, obesity, diabetes mellitus, and CAH are predictive of concurrent endometrial carcinoma in endometrial hyperplasia patients. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Our objective was to determine whether RUNX3 tumor suppressor is inactivated in endometrial carcinoma. Methods: We have investigated 24 endometrial carcinomas, 3 endometrial carcinoma cell lines, and 9 normal endometria for genetic and epigenetic alterations of RUNX3. Reverse-transcription PCR (RT-PCR), methylation-specific PCR (MS-PCR) analysis, and loss of heterozygosity (LOH) analysis were performed. We also tested RUNX3 protein expression by immunohistochemistry. Results: Using RT-PCR technique, we observed a significant loss of RUNX3 mRNA expression in nine of 24 endometrial carcinomas (38%) and in all 3-cell lines (100%). In contrast, all nine of the normal endometria showed an abundant expression of RUNX3 mRNA. Methylation-specific PCR (MS-PCR) analysis of the CpG islands of RUNX3 showed the promoter region to be hypermethylated in 18 of 21 analyzed carcinomas (86%), whereas only two of nine normal endometria (22%) were methylated (p <0.01). By using two polymorphic microsatellite markers, D1S199 and D1S1676, we detected 1p36 LOH in 7 of 21 carcinomas (33%). We observed a significant relationship between the loss of RUNX3 mRNA expression and this regional LOH (p <0.01). Immunohistochemical staining showed that RUNX3 protein expression was lost in 12 of 21 endometrial carcinomas (57%). We observed a significantly more frequent loss of RUNX3 protein expression in the histologically higher-grade tumors (Grade 3) than in Grade 1 or 2 tumors (p <0.01). Conclusion: These findings indicate that RUNX3 inactivation may play an important role in carcinogenesis of the endometrium, especially in high-grade endometrial carcinoma. [Copyright &y& Elsevier]